In prior arts, rhein or rhein analogues has been used in the preparation of various drugs, for instance, a rhein salt disclosed in Chinese patent 200410049948, which is shown in the following two general formulae respectively:
Where, M is alkali metal, alkaline-earth metal or organic alkali residues.
Rhein analogues are defined as matters extracted, refined or chemically modified form the rhein or rhein analogues such as rhubarb (Rheum palmatum L., Rheum tanguticum Maxim. Ex Balf. Or Rheum officinale Baill., Polygonum cuspidatum (Polygonum cuspidatum sieb. Et Zucc.), Folium sennae (Folium sennae), etc. The characteristic composition is rhein or rhein analogues -containing effective part, shown as the compounds with general formula (I).
According to patent search data from Chinese Pharmaceutical Abstracts (searching word “Rhein”), CNKI database (searching word “Rhein”), China patent (searching word “Rhein”), CA (Search “Accession No. 478-43-3”), US Patent (searching word “Rhein”) and European Patent (searching word “Rhein”), the salts of rhein analogues include rhein sodium salt, rhein potassium salt (U.S. Pat. No. 6,197,818, CN97107137), and diacerhein [13739-02-1] (CN97192531, CN93101181, CA96: 193416) and diacerhein potassium salt (EP243968).
Diabetes is a systemic metabolic disease, despite many factors involved in the pathogenesis, insulin resistance (IR) and pancreatic β cell dysfunction are considered to be the two main components. Obesity, hypertension, hyperlipidemia, hyperuricemia and hypercoagulable state constitute IR clinical syndromes. IR often exists prior to the existence of reduction of sugar tolerance, which is not only the direct reason for the occurrence of diabetes, but also the basis of cardiovascular complications of diabetes. Diabetic nephrosis (DN) is a common complication of diabetes. Rhein has multiple functions in the aspects of sugar reduction, lipid adjustment, and improvement of insulin resistance and reduction of the urine protein excretion and so on; therefore, it can play a multi-target, multi-layered role in different phases of diabetic nephrosis, so as to achieve the purpose of prevention and treatment of diabetic nephrosis.
Abdominal surgery is the most common surgical operation. Generally the patients after operation have relatively weak gastrointestinal function; therefore, the recovery of gastrointestinal function after surgery has great significance on the patient's rehabilitation, including the recovery of diseases and reduction of complications such as intestinal adhesion, etc.
Postoperative intestinal adhesion is still an unresolved clinical surgical problem. The research reports in recent years show that 90%˜100% of patients of abdominal surgery will produce postoperative intestinal adhesion [Luijendijk R W, etal Foreign material in postoperative Adhesions AnnSurg, 1996,223(3):242; Scott Coombers D.etal Human intraperitoneal fibrinolytic respond to elective surgery BrJSurg, 1995,82:414]. Among the patients of adhesions, more than 80% of patients will form adhesions between wounds and omentum, and 50% of cases involve in small intestine [Menxies D, etal Intestinal obstruction from adhesions: How big is the problem? AnnR Coll Surg Engl, 1990, 72 (1): 60]. And the occurrence of intestinal adhesion is related to post-operative peritoneal exudation and weak enterokinesia. Reduction of exudation or improvement of enterokinesia will reduce the occurrence of adhesions. Currently the gastrointestinal dynamic drugs have strong action on the stomach and intestines, especially on the stomach, which will easily cause abdominal discomfort and vomiting. Although the medicines promoting enterokinesia can accelerate the enterokinesia, it cannot reduce the inflammatory reaction and the exudation of inflammatory substances and fibrins.
Neostigmine Bromide can cause the obvious anastalsis in the clinical application, and patients have obvious pain feeling, which cannot actually allow the recovery of gastrointestinal function [Liqishen, et al. The clinical observation of the use of rhubarb on the intestinal function recovery of postoperative patients of diffuse peritonitis, Chinese Journal of Coal Industry Medicine, 1998, 1 (4): 372)]. Clinically raw rhubarb liquid is administered [Ge Hengwen et al, clinical effect observation of recovery of postoperative gastrointestinal function of raw rhubarb liquid, Journal of Hubei Medical Staff College, 2002,15 (2), 19], or rhubarb and other traditional Chinese drug are decocted and orally administered [Huang Honghan, Clinical application study of intestinal adhesion soup, Traditional Chinese Medicine Journal 2006,5 (2), 42]. However, the clinical dose is difficult to control, and administration is inconvenient, so it is subject to restriction for clinical use.
Osteoarthritis, rheumatic arthritis and rheumatoid arthritis are higher incidence of arthrosis. Taking the former as an example, the incidence rate is about 10 percent of the total population, and for patients over 60 years old, over 50 percent of patients are affected, and for women under 45 years old, 45-60 years old and over 65 years old, the incidence rate is 2%, 30% and 68% respectively; for men, the rate is 3%, 24.5% and 58% respectively. With the ageing of the population, the morbidity is becoming more and more in the total population. At present, the main drugs for treatment of osteoarthritis mainly include steroid and non-steroid anti-inflammatory drugs. The adverse reaction of steroid anti-inflammatory drugs is generally known for the public. For the non-steroid anti-inflammatory drugs, cyclooxygenase inhibitor (COX) also has many adverse reactions, for instance, oral administration and injection will cause alimentary tract hemorrhage, and especially old people may produce adverse reactions, which is unfavorable for the diseases of high incidence for old people such as osteoarthritis.
Because rhein analogues are indissoluble in the water and cannot be completely absorbed by the gastrointestinal tract, the bioavailability becomes low which makes restriction on the application of the rhein. The salt formation by combination of rhein analogues and metal ion increases the water solubility of rhein compounds, improves the bioavailability of oral administration; because the rhein sodium salt, rhein potassium salt (U.S. Pat. No. 6,197,818, CN97107137), and diacerhein [13739-02-1] (CN97192531, CN93101181, CA96: 193416) and diacerhein potassium salt (EP243968) are strong base- weak acid salt, the solution presenting basicity, if made into hydro-acupuncture, the pH value is higher, which is unacceptable for human physiology; while if decreasing the pH value, the stability of the preparation is bad.